Delayed mTOR Inhibition with Low Dose of Everolimus Reduces TGFβ Expression, Attenuates Proteinuria and Renal Damage in the Renal Mass Reduction Model

Abstract. The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164 ± 5 [Wistar-Furth] versus 184 ± 7 [Wistar] mmHg mean arterial pressure), with sham animals remaining normotensive (134 ± 6 mmHg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7 ± 4.2 [Wistar-Furth] versus 97.4 ± 22.6 [Wistar] mg/d per 100 g body wt, P < 0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats (P < 0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144 ± 8 mmHg [Wistar] versus 157 ± 7 mmHg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction.

Download Full-text

Faculty Opinions recommendation of V1/V2 Vasopressin receptor antagonism potentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1180956.643054 ◽

2009 ◽

Author(s):

Mai Ots-Rosenberg

Keyword(s):

Renal Mass ◽

Renin Angiotensin System ◽

Vasopressin Receptor ◽

Mass Reduction ◽

Angiotensin System ◽

Receptor Antagonism ◽

Renin Angiotensin ◽

V2 Vasopressin Receptor

Download Full-text

Progressive Reduction in Mitochondrial Mass Is Triggered by Alterations in Mitochondrial Biogenesis and Dynamics in Chronic Kidney Disease Induced by 5/6 Nephrectomy

Biology ◽

10.3390/biology10050349 ◽

2021 ◽

Vol 10 (5) ◽

pp. 349

Author(s):

Rodrigo Prieto-Carrasco ◽

Fernando E. García-Arroyo ◽

Omar Emiliano Aparicio-Trejo ◽

Pedro Rojas-Morales ◽

Juan Carlos León-Contreras ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Mitochondrial Biogenesis ◽

Renal Mass ◽

Renal Damage ◽

Peroxisome Proliferator ◽

Progressive Reduction ◽

Ckd Progression ◽

Peroxisome Proliferator Activated Receptor ◽

Mitochondrial Mass ◽

Mitochondrial Impairment

The five-sixth nephrectomy (5/6Nx) model is widely used to study the mechanisms involved in chronic kidney disease (CKD) progression. Mitochondrial impairment is a critical mechanism that favors CKD progression. However, until now, there are no temporal studies of the change in mitochondrial biogenesis and dynamics that allow determining the role of these processes in mitochondrial impairment and renal damage progression in the 5/6Nx model. In this work, we determined the changes in mitochondrial biogenesis and dynamics markers in remnant renal mass from days 2 to 28 after 5/6Nx. Our results show a progressive reduction in mitochondrial biogenesis triggered by reducing two principal regulators of mitochondrial protein expression, the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and the peroxisome proliferator-activated receptor alpha. Furthermore, the reduction in mitochondrial biogenesis proteins strongly correlates with the increase in renal damage markers. Additionally, we found a slow and gradual change in mitochondrial dynamics from fusion to fission, favoring mitochondrial fragmentation at later stages after 5/6Nx. Together, our results suggest that 5/6Nx induces the progressive reduction in mitochondrial mass over time via the decrease in mitochondrial biogenesis factors and a slow shift from mitochondrial fission to fusion; both mechanisms favor CKD progression in the remnant renal mass.

Download Full-text

RENAL MASS REDUCTION INCREASES THE RESPONSE TO EXOGENOUS INSULIN INDEPENDENT OF ACID-BASE STATUS OR PLASMA INSULIN LEVELS IN RATS.

AJP Renal Physiology ◽

10.1152/ajprenal.00679.2020 ◽

2021 ◽

Author(s):

Elinor C Mannon ◽

Christina L Sartain ◽

Trevin C Wilkes ◽

Jingping Sun ◽

Aaron J Polichnowski ◽

...

Keyword(s):

Metabolic Acidosis ◽

Insulin Sensitivity ◽

Renal Mass ◽

Plasma Insulin ◽

Exogenous Insulin ◽

Mass Reduction ◽

Sham Control ◽

Acid Base ◽

Plasma Insulin Levels ◽

Remnant Kidney

Impairments in insulin sensitivity can occur in patients with chronic kidney disease (CKD). Correction of metabolic acidosis has been associated with improved insulin sensitivity in CKD, suggesting metabolic acidosis may directly promote insulin resistance. Despite this, the effect of acid or alkali loading on insulin sensitivity in a rodent model of CKD (remnant kidney) has not been directly investigated. Such studies could better define the relationship between blood pH and insulin sensitivity. We hypothesized that in remnant kidney rats, acid or alkali loading would promote loss of pH homeostasis and consequently decrease insulin sensitivity. To test this hypothesis, we determined the impact of alkali (2 weeks) or acid (5-7 days) loading on plasma electrolytes, acid-base balance, and insulin sensitivity in either sham control, 2/3 or 5/6 nephrectomy rats. Rats with 5/6 nephrectomy had the greatest response to insulin followed by animals with 2/3 nephrectomy and sham control rats. We found that treatment with a 0.1M sodium bicarbonate solution in drinking water had no effect on insulin sensitivity. Acid loading with 0.1M ammonium chloride resulted in significant reductions in pH and plasma bicarbonate. However, acidosis did not significantly impair insulin sensitivity. Similar effects were observed in Zucker obese rats with 5/6 nephrectomy. The effect of renal mass reduction on insulin sensitivity could not be explained by reduced insulin clearance or increased plasma insulin levels. We found that renal mass reduction alone increases sensitivity to exogenous insulin in rats, and that this is not acutely reversed by development of acidosis.

Download Full-text

Effects of growth hormone and IGF-I on renal function in rats with normal and reduced renal mass

AJP Renal Physiology ◽

10.1152/ajprenal.1990.259.5.f747 ◽

1990 ◽

Vol 259 (5) ◽

pp. F747-F751 ◽

Cited By ~ 3

Author(s):

S. B. Miller ◽

V. A. Hansen ◽

M. R. Hammerman

Keyword(s):

Growth Hormone ◽

Renal Function ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Renal Mass ◽

Filtration Rate ◽

Inulin Clearance ◽

Mass Reduction ◽

Contralateral Kidney ◽

Igf I

To characterize actions of growth hormone (GH) and insulin-like growth factor ( (IGF-I) on renal function in rats with normal and reduced renal mass, we administered recombinant bovine growth hormone (bGH) or human IGF-I (hIGF-I) to normal rats or to rats that had undergone unilateral nephrectomy and two-thirds infarction of the contralateral kidney, and measured inulin and p-aminohippurate clearances over 10-17 days. Administration of either bGH (100-200 micrograms/day) or hIGF-I (200 micrograms/day) to rats with normal renal mass increased inulin and p-aminohippurate clearances compared with those measured in animals that received vehicle. Filtration fractions were not affected by either bGH or hIGF-I. Inulin clearance was decreased to approximately 17% of normal 1 day after reduction of renal mass in rats. Over the next 3 days insulin clearance increased significantly in rats with reduced renal mass that were administered vehicle. No further enhancement occurred during the next 7 days. Neither bGH nor hIGF-I affected inulin clearance in rats with reduced renal mass. We conclude that both GH and IGF-I enhance glomerular filtration rate when administered to rats with normal renal mass, but not when administered in the same quantities to rats in which renal functional mass is reduced. Glomerular filtration rate increases within 4 days of renal mass reduction independent of exogenous GH or IGF-I.

Download Full-text

MYH9 E1841K Mutation Augments Proteinuria and Podocyte Injury and Migration

Journal of the American Society of Nephrology ◽

10.1681/asn.2015060707 ◽

2017 ◽

Vol 29 (1) ◽

pp. 155-167 ◽

Cited By ~ 17

Author(s):

Sylvia Cechova ◽

Fan Dong ◽

Fang Chan ◽

Michael J. Kelley ◽

Phillip Ruiz ◽

...

Keyword(s):

Kidney Disease ◽

Renal Mass ◽

High Salt ◽

Missense Mutations ◽

Ang Ii ◽

Mass Reduction ◽

Functional Variants ◽

Induced Hypertension ◽

And Migration

Intronic variants of the MYH9 gene that encodes the nonmuscle myosin heavy chain IIA are associated with diabetic nephropathy in European Americans and with sickle cell disease–associated nephropathy. However, the causal functional variants of MYH9 have remained elusive. Rare missense mutations in MYH9 cause macrothrombocytopenia and are occasionally associated with development of nephropathy. The E1841K mutation is among the common MYH9 missense mutations and has been associated with nephropathy in some carriers. To determine the contribution of the E1841K mutation in kidney disease, we studied the effects of the E1841K mutation in mice subjected to high salt or angiotensin II (Ang II) as models of hypertension and in mice subjected to renal mass reduction as a model of CKD. Despite similar levels of BP among wild-type (MYH9+/+) mice and mice heterozygous (MYH9+/E1841K) and homozygous (MYH9E1841K/E1841K) for the mutation in each model, MYH9E1841K/E1841K mice exhibited mildly increased albuminuria in response to high salt; severe albuminuria, nephrinuria, FSGS, and podocyte foot effacement in Ang II–induced hypertension; and early mortality in the renal mass reduction model. Treatment with candesartan during Ang II–induced hypertension attenuated kidney disease development in MYH9E1841K/E1841K mice. In vitro, isolated primary podocytes from MYH9E1841K/E1841K mice exhibited increased lamellipodia formation and reorganization of F-actin stress fibers. Wound healing assays revealed that MYH9+/+ podocytes had the lowest migration rate, followed by MYH9+/E1841K then MYH9E1841K/E1841K podocytes. In conclusion, the MYH9 E1841K variant alters podocyte cytoskeletal structure and renders podocytes more susceptible to injury after a damaging stimulus.

Download Full-text